DESCRIPTION: Recent evidence supports the idea that B cell hyperactivity in SLE is T cell driven; however, studies of T cell function in SLE patients have yielded two robust yet paradoxical findings: increased T helper (Th) cell function in conjunction with reduced cytotoxic T cell (CTL) function. A central unresolved question in SLE is whether increased Th cell function results from a primary, permissive defect in CMI or whether, based on the ability of Th1 and Th2 cells to cross regulate each other, impaired CMI is a secondary consequence of persistent Th cell activation. The two possibilities are not mutually exclusive and evidence exists to support the latter possibility. The former possibility has been difficult to address in humans but can be directly tested in an induced model of murine SLE, the parent-into-F1 model of chronic graft-versus-host disease (GVHD). Based on our published work and preliminary data in this model, the principal investigator has constructed a novel hypothesis regarding the role of CTL in SLE development. Specifically, we hypothesize that CD8+ CTL play a critical role in eliminating auto-reactive B cells and that SLE can develop when activated CD4+ Th cells specific for auto-reactive B cells arise in the setting of defective CTL function. By extension, agents that inhibit the development of mature CTL effectors will predispose to SLE whereas agents that promote CTL effector development will inhibit SLE development. The overall goal of this proposal is to identify the mechanisms critical for in vivo CTL development and identify which defects in CTL maturation and/or function will result in SLE. Using the parent-into-F1 model of SLE GVHD, the investigator will test these hypotheses in the following specific aims. Specific Aim 1: Identify the co-stimulatory molecules critical for CD8+ T cell activation and CTL induction. Specific Aim 2: Determine how IFN-g, IL-2, TNF-a, and IL-12 regulate CTL development and how defects in these cytokines result in SLE. Specific Aim 3: Define the contributions of perforin and Fas/FasL to T cell elimination of auto-reactive B cells in acute GVHD and the consequences of defects in these pathways. By defining the in vivo mechanisms that can promote SLE we will identify potentially new therapeutic approaches for human SLE.